Sunday, June 2, 2013

Gut and Brain Again

A long time ago, when I was an intern, I would drive into the hospital for ultra long shifts. Day went into night into the next day. You might be lucky to get one day off in a month. It's illegal now to work interns as much as we were worked, and I understand the sleep science behind the laws. But at the same time, you learn something about yourself and your patients in the long march over a day and a night and a day.

Bono says this song is about a hangover. I used to listen to it on repeat during that sleep-deprived drive into work for those long, long days. In A Little While. I would close my eyes on the elevator in the hospital and hear it playing in my head. Right now I am working a great deal on various projects and of course with my clinical practice. I hope to get a little bit of a break before too long…and have time to do more fun and interesting reading and blogging.

When we are born, we are colonized by the first generation of those eventual 100 trillion bacteria from nearly 1000 differenct species that makes up 90% of the cells of our body. These cells communicate with our brain and likely affect our behavior. The organisms help us to break down complex polysaccharides and they are critical to the normal development of the immune system. A relatively new paper reviews how they might influence anxiety and depression (1).

The mircobiome is influenced by age, diet, stress, metabolism, antibiotics, geography, and genetics. As regards stres reponse, mice lacking a microbiome have an exaggerated hypothalamic-pituitary-adrenal response to stress compared to mice normally colonized. The mircobiome seems to play a role in programming stress response from the very beginning. Stress will also increase intestinal permeability, which gives the bacteria of the microbiome greater access to communicate via inflammation and the enteric nervous system. Microbes can communicate with the human brain via various neurotransmitters, such as GABA, and there is also evidence that different gut bacteria have different effects on serotonin signalling in the central nervous sysem (at least in mice).

When pathogenic bacteria are introduced into the gut of mice, a robust central nervous system response is evident via the vagus nerve, followed by a systemic inflammatory response. Friendlier bacteria (such as lactobacilli) also elicit a central nervous system response, but not the systemic inflammation. Also in mice, certain neurons of the enteric nervous system change how excitable they are (or how easily they signal) depending upon the species of bacteria in the gut. Now repeated in many studies, the infection of mice with pathogenic bacteria increases anxiety-like behavior and treatment with friendly gut bacteria reverses the change in behavior. In some of these studies, changes in the production of nerve fertilizer (so to speak), brain-derived neurotrophic factor, matched the increases and decreases in anxiety-like behavior. The friendly bacteria are associated with greater nerve plasticity and repair, whereas the pathogenic bacteria showed the opposite.

In humans, there are few studies, and none in people diagnosed with clinical anxiety or depression. However, in a double-blind placebo controlled trial of probiotics given for 30 days (2), healthy volunteers who took the probiotic showed significantly less psychological distress than those who didn't. Another three week study showed the healthy volunteers with the most depression-like symptoms had significant improvement on a probiotic while those who took placebo had no benefit (3). There are also positive studies showing probiotics impacting anxiety symptoms in people with Chronic Fatigue Syndrome and undergoing cancer treatment.

Many questions remain that must be further studied. There are differences in how easily the gut microbiome is changed in different life periods, with childhood perhaps showing more amenability to change. In adults it is likely that fecal transplants and the introduction of chronic parasitic infection are the only practical way to permanently affect the microbiome. Childhood exopsure to antibiotics and probiotics may have different consequences than adult exposure to the same.

13 comments:

Emily, do we understand why the microbiome in a child is more easily changed as in an adult? Would a change in your diet not affect the microbiome, also in an adult?

A microbiome is an ecosystem. For ecosystems not only the averages (average temperature, precipitation, soil moisture, etc.) are important, but also their variability (extremes (dry periods, floods, freezing), daily and annual cycle). Do you know of any research on the importance of variability for the microbiome?

@Victor most of that was determined by mouse studies, where mice were born germ-free, then colonized during infancy, adolescence, or adulthood, and there seemed to be a critical period of childhood and adolescence where changes could be affected. There are also sexual differences in mice but I didn't go into that in my post. That could be possibly relevant to humans in autism syndromes where gut dysbiosis is a known part of the disorder and boys are more vulnerable.

This looks like a very promising series on this topic: http://www.gutpathogens.com/content/5/1/5

Mental health disorders, depression in particular, have been described as a global epidemic. Research suggests that a variety of lifestyle and environmental changes may be driving at least some portion of the increased prevalence. One area of flourishing research involves the relationship between the intestinal microbiota (as well as the related functional integrity of the gastrointestinal tract) and mental health. In order to appreciate the recent scientific gains in this area, and its potential future directions, it is critical to review the history of the topic. Probiotic administration (e.g. Lactobacillus) and fecal microbiota transfer for conditions associated with depression and anxiety is not a new concept. Here, in the first of a 3-part series, we begin by reviewing the origins of the contemporary research, providing a critical appraisal of what has become a revisionist history of the controversial term ‘autointoxication’. We argue that legitimate interests in the gut-brain-microbiota connection were obscured for decades by its association with a narrow historical legacy. Historical perspectives provide a very meaningful context to the current state of the contemporary research as outlined in parts II and III.

"Mental health disorders, depression in particular, have been described as a global epidemic."Could a possible cause be: increasing belief that the world is going to hell in a hand-cart (e.g. due to seeing too much "bad news" in the media)?

I couldn't find the reference for the first footnote you had at the end of paragraph 3. Which article or study is that from? I find this subject really fascinating and can see it being a larger issue in the future in terms of evaluating one's overall health (http://wp.me/p1Xyqa-4H).

This subject has dominated my life and that of someone very close to me for almost three years. My then 13 year old daughter took minocycline, her first ever antibiotic and our lives changed it seems forever. Within a fortnight our happy, bubbly extrovert became a severely anxious, depressed girl that cried 24/7 and eventually had to be taken out of school. Long story short no doctor would believe it could be the antibiotic (even though "mental changes" is a listed side effect), so she was admitted to the mental health system. She has been admitted to hospital about eight times in ten months and had about ten blood tests. No one identified that she had severe deficiencies in chromium and iron and borderline zinc and selenium. Two and a half years in and we found a doctor who believed her microbiome had been changed by the antibiotic. He quickly identified her deficiencies with a more comprehensive blood test and gave us a specially prepared mineral supplement. Good News? It would have been except that she is now in the involuntary care of the mental health team. When presented with a trial of zero risk option A) A Mineral Supplement and higher risk option B) Atypical antipsychotics they went with option B. Frustratingly When they gave her an iron supplement prior to her appointment for an infusion, she improved dramatically and immediately, but they are still not at all motivated to give her our doctor's prescription. This is a never ending nightmare and we are stuck between two medical factions with vastly different opinions.

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About Me

Emily Deans, M.D.: I'm a psychiatrist in Massachusetts searching for evolutionary solutions to the general and mental health problems of the 21st century. Disclaimer: This information is for educational purposes only, and is in no way intended to be personal medical advice. Please ask your physician about any health guidelines seen in this blog, as everyone is different in his or her medical needs.